The present invention relates to methods for treating glaucoma or improving accommodation (i.e. the process by which the eye adjusts for vision at different distances). In one aspect, the present invention relates to a method of decreasing the intraocular pressure caused by glaucoma.
Diabetes is the major determinant to the development of visual disability and blindness in parts of the world unencumbered by causes related to malnutrition or infectious diseases. Retinopathy is the leading cause of blindness in diabetics and is a progressive, degenerative disease. Of the many risk factors believed to be associated with diabetic retinopathy, the level of glucose in the plasma has been widely investigated. It is well accepted that a lower incidence of retinopathy is associated with decreased plasma levels of glucose.
Ophthalmologic disorders in diabetes include opacification and glaucoma. The occurrence of these indications is correlated with the persistent hyperglycemia of the disease. Although the incidence of glaucoma is significant in diabetic populations, glaucoma affects a substantial portion of the general aging population as well.
Primary open angle glaucoma occurs in approximately 4% of diabetics compared to 1.8% of the general population. The reasons for the increase in intraocular pressure that is observed in this disorder are not completely understood. The increase in intraocular pressure that characterizes glaucoma is likely caused by an impairment in the drainage of fluid from the eye at the trabecular meshwork since trabeculectomy restores, at least for a period of time, normal intraocular pressures. The origin of this impairment to fluid movement is currently unknown but may be related to a physical obstruction or restriction to movement of proteins that make up a sieving system in the trabecular meshwork. The trabecular meshwork functions as a sieving system that maintains a restricted flow of intraocular fluid from the eye. The result of excess restriction of this flow is a back pressure that causes increased intraocular pressure.
Replacement of the trabecular meshwork (trabeculectomy) remains an established surgical procedure for improving the filtering of intraocular fluid and for overall reduction of intraocular pressure. This remedy is invasive and of limited effectiveness, since pressure elevation frequently recurs after the procedures.
Current chronic pharmaceutical therapies impose a measure of risk on an already medically compromised patient population. The use of topical B-blockers may affect underlying cardiovascular disease, and carbonic anhydrase inhibitors (e.g. Diamox(trademark)) may cause metabolic acidosis. The use of pressure-lowering drugs will be affected by the state of renal disease in compromised elderly and diabetic patients. The drawbacks associated with current pharmaceutical therapies highlight an unmet medical need for a chronic pharmaceutical intervention that is distinct in mechanism of action from current therapies.
New strategies for pharmaceutical intervention in the treatment of glaucoma based upon new mechanisms of action need to be identified. In addition, pharmaceutical agents that decrease the intraocular pressure associated with glaucoma are needed. Also, the methods of improving accommodation provided by the invention allow one to avoid costly and burdensome optical solutions, such as the use of separate reading glasses or glasses with bifocal lenses.
In one embodiment, the invention relates to a method of treating or ameliorating or preventing glaucoma, decreasing intraocular pressure or improving or ameliorating ocular accommodation in an animal, including a human, comprising administering an intraocular pressure decreasing or ocular accommodation improving amount of a compound of the formula I: 
wherein: W and Y are independently N or, respectively, CRW or CRY. Z is O, S or NRZ. Q is xe2x80x94CH2xe2x80x94 or xe2x80x94(CO)xe2x80x94CH2xe2x80x94, where the methylene is bonded to a ring nitrogen. RW and RY are independently hydrogen, alkyl, xe2x80x94Cxe2x89xa1CRE, xe2x80x94CH2xe2x80x94Cxe2x89xa1CRP, alkenyl, aryl, arylalkyl, aryloxy, arylthio, amino, alkylamino, arylamino, dialkylamino, diarylamino, CH3C(O)NHxe2x80x94, fluoroalkyl, perfluoroaryl, hydroxyalkyl, C(O)NH2, and S(O)2NH2 or, together with their ring carbon atoms form a fused 6-membered aromatic or heteroaromatic ring, wherein RE or RP is alkyl, hydrogen, hydroxyalkyl or aryl. RZ is alkyl, xe2x80x94CH2xe2x80x94Cxe2x89xa1CRP, aryl, arylalkyl, or aroylalkyl. R1 and R2 are independently hydrogen, alkyl or hydroxymethyl. R3 is hydrogen or methyl. R4 is acetamido, hydrogen, methyl, amino, xe2x80x94Cxe2x89xa1CRE, xe2x80x94CH2xe2x80x94Cxe2x89xa1CRP alkylthio, fluoromethyl, difluoromethyl, trifluoromethyl, cyanomethyl, hydroxyalkyl, alkoxycarbonyl-methyl, 1-(alkoxycarbonyl)-1-hydroxyalkyl or aminocarbonylmethyl. (The xe2x80x9c1xe2x80x9d notations of xe2x80x9c1-(alkoxycarbonyl)-1-hydroxyalkylxe2x80x9d indicates that a terminal methyl [but for the recited substitutions] of xe2x80x9calkylxe2x80x9d is substituted with the hydroxyl and esterified carbonyl.)